# Advances in Gene Therapy for Inherited Haemoglobinopathies

## TL;DR

This paper reviews recent progress in gene therapy for inherited blood disorders like β-thalassaemia and sickle cell disease, highlighting new treatments and challenges in making them widely available.

## Contribution

The paper provides an updated overview of gene therapy advancements, including CRISPR-based approaches and strategies to increase hemoglobin production.

## Key findings

- Lentiviral gene addition therapies have achieved transfusion independence in β-thalassaemia and reduced pain crises in sickle cell disease.
- CRISPR/Cas9 gene editing has led to the first approved therapy for sickle cell disease and β-thalassaemia by targeting γ-globin repression.
- Base editing technologies are emerging as more precise tools for genetic modification in treating haemoglobinopathies.

## Abstract

Haemoglobinopathies, including β-thalassaemia and sickle cell disease (SCD), are among the most common monogenic disorders worldwide and remain major causes of morbidity and early mortality. Historically, management of these life-altering diseases has relied on supportive treatment and symptom management and, although these treatments reduce symptoms and ease disease burden, they do not correct the underlying genetic defect. Allogenic haematopoietic stem cell transplantation (HSCT) has been the only established curative option; however, it comes with substantial risks that significantly restrict its applicability. Over the past two decades, haematopoietic stem cell (HSC) gene therapy for haemoglobinopathies has rapidly progressed from experimental proof-of-concept to approved therapies. Lentiviral gene addition approaches have demonstrated durable expression of functional β-like globin transgenes, achieving transfusion independence in β-thalassaemia patients and significant reductions in vaso-occlusive events in SCD patients. Alternative therapeutic approaches to promote HbF expression have proved to be highly successful. Gene silencing strategies targeting BCL11A have been successful clinically and, more recently, gene editing technologies such as CRISPR/Cas9 have enabled precise disruption of regulatory elements controlling γ-globin repression, leading to the approval of the first CRISPR-based therapy for SCD and β-thalassaemia. Emerging base editing technologies promise even more precise genetic modification and are advancing through clinical evaluation. Despite these advances, access to gene therapy remains restricted due to the need for highly specialised manufacturing, toxic myeloablative conditioning regimens, and high treatment costs. Ongoing improvements and adaptations in these areas are essential to ensure that gene therapies fulfil their potential as accessible, curative treatments for patients suffering from haemoglobinopathies worldwide.